FDA 483’s and Warning Letters

Your company has just been inspected by the US Food and Drug administration (FDA) Office and the FDA inspectors handed over an FDA Form 483 at the end of the inspection. What does that mean for your company? Is this what they call the “FDA Warning Letter”?

This blog is about FDA Forms 483 (“FDA 483”) and Warning Letters, and how to deal with these documents.

FDA Form 483

An FDA 483 is a summary that will be issued by the FDA inspectors at the conclusion of an inspection. This form may or may not be issued; however, when your company receives an FDA 483, it means that the inspectors have, as the FDA states, “observed any conditions that in their judgement may
constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts”(1). This is not the notorious Warning Letter, at least not yet!

When your company receives an FDA 483 at the end of an inspection, it means that issues are observed which require action(1). It is prudent to act immediately, since an adequate response to the FDA, usually required within 15 business days, may prevent you from a far worse situation.

The recommended steps are:

  • Establish a team with adequate resources and expertise in the area(s) of attention, with sufficient power to take any decisions and fully supported by leadership.
  • Review the observations carefully and the related documentation to assess and understand what has been said, and perform a root cause analysis.
  • Create a thorough response to the FDA, including a corrective action plan with realistic timelines for each observation.
  • Make it clear in your responses that the FDA’s concerns are taken very seriously and you show commitment to patient safety and quality of your product or services.
  • In case you feel that one of the observations is incorrect, carefully choose your wording and try to justify with supporting evidence. When no evidence can be provided, re-consider the statement that you disagree with the observation.
  • Before the response is sent out to the FDA, make sure it is reviewed by a team of knowledgeable people.
  • Make sure you take corrective actions as promised to the FDA, and try to meet the timelines. If the FDA returns, you should be able to show you have followed the proposed plan.

A thorough and adequate response to the FDA 483 is important, since it will be taken into consideration by the FDA, when they review all collected information around an inspection to determine whether additional measures need to be taken(1). Those measures may have large consequences for the company. The FDA may decide that immediate enforcement actions are required (such as a recall, a seizure, penalties or a prosecution)1. The FDA can also issue a Warning Letter.

FDA Warning Letter

In case the FDA defines that violations of regulatory significance have taken place, they may decide to issue a Warning Letter(2). A Warning Letter may be issued to allow a company to take voluntary action FDA WARNING LETTER AND FDA FORM 483(2) to get back into compliance with the FD&C or related Acts(2). Warning Letters are made publicly available on the FDA website.

When a Warning Letter is issued as a result of an inspection, it means that, even though the company might have responded to the FDA 483, the FDA feels that violations of regulatory significance have taken place and further action is required. This may be a consequence of the type of observations or the response to the FDA 483 was deemed inadequate and will require further action.

A thorough, complete response to the Warning Letter may prevent the company from further damage. A plan to act and respond promptly to a Warning Letter, again usually within 15 business days, may therefore require further investigation, an even larger team and a comprehensive action

Once a Warning Letter has been issued, your company is on the radar of the authorities and your customers. You may need to be prepared for more regulatory inspections, and you should also be prepared for the potential direct and indirect financial consequences.

How to avoid an FDA 483 and/or Warning Letter?

A company can take measures to avoid a negative inspection outcome. It is important to know the business, to know your company and staff and to know your company’s weaknesses and challenges.
Being ready for inspections at any time, will increase your company’s chance for a positive inspection outcome.

Permanent inspection-readiness can be established by processes to ensure and assure quality of the product or services, such as:

  • An up-to-date and a GxP compliant quality management system
  • A qualified IT infrastructure with validated computerized systems
  • Validated and qualified equipment and processes
  • A robust supplier quality management process
  • Regular training of staff according to the latest GxP standards
  • Adequate quality control
  • A fit-for-purpose (risk-based) audit program
  • A regular proactive risk assessment of process performance and product quality to ensure continual improvement of your business(3)

In addition, inspection preparedness activities may support the company to be “physically and mentally” ready for any inspection. Such activities may include:

  • Develop a standardized procedure and script for facilitation of inspections
  • Train staff how to approach and how to behave during an inspection
  • Perform regular checks of facilities and relevant documentation, including retrieval of documentation from archives
  • Perform a mock inspection to test the script and to assess whether staff and facilities are ready to receive an inspection
  • Take immediate corrections or corrective actions in case (significant) non-compliance has been identified
  • Use a mock inspection as an opportunity to identify potential risks and take appropriate
    preventive actions to ensure continual improvement of your company’s product and processes(3)

Inspection Readiness

Rescop can offer support to your company in any permanent inspection-readiness or inspection preparedness activities prior to an inspection. We can also support your company in setting up a corrective action plan after an inspection and responding to the FDA in case you have received an FDA Form 483 or Warning Letter.

Rescop has Consultants and Auditors available who have experience with multiple regulatory agencies and expertise in the following fields:

  • GMP – Good Manufacturing Practice
  • GDP – Good Distribution Practice
  • GLP – Good Laboratory Practice
  • GCP – Good Clinical Practice
  • Information Technology (including CISA-certified auditors)
  • Computer System Validation (including GAMP5 and Agile)
  • Medical Devices

Further reading / References:

1) FDA Form 483 Frequently Asked Questions, FDA (last updated 23 Apr 2015) [online]. Click here to visit.

2) 4-1 – WARNING LETTERS, FDA (last updated 02 May 2016) [online]. Click here to visit.

3) FDA Guidance for Industry Q10 Pharmaceutical Quality System (ICH Q10), FDA (April 2009) [online]. Click here to visit.

Author: Henrieke de Bie, Principal Consultant, Rescop BV